AXL, a receptor tyrosine kinase, contributes to tumor cell invasion, dedifferentiation, and drug resistance. Mechanisms governing AXL protein abundance are incompletely understood, and identifying AXL regulators could elucidate novel therapeutic targets. To that end, Schieven and colleagues performed a whole-genome CRISPR-Cas9 screen in a melanoma cell line and measured subsequent AXL protein expression using flow cytometry. Single-guide RNA (sgRNA) sequencing in cells sorted based on high and low AXL expression revealed that 5 members of the Elongin BC ubiquitin ligase complex—ELOB, ELOC, SOCS5, UBE2F and RNF7—negatively regulate AXL abundance. Pharmacologic inhibition of neddylation and proteosomal degradation increases AXL expression significantly more in control cells than cells expressing ELOB-targeting sgRNA, demonstrating that a functional Elongin BC complex promotes AXL degradation. Transcriptional and IHC analyses show that Elongin B/C expression positively correlates with melanoma differentiation status. Lastly, pharmacologic BRAF or MEK inhibition suppress Elongin C expression while augmenting AXL expression. Taken...
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1 May 2023
Highlights|
May 01 2023
Selected Articles from This Issue
Online ISSN: 1557-3125
Print ISSN: 1541-7786
©2023 American Association for Cancer Research
2023
American Association for Cancer Research
Mol Cancer Res (2023) 21 (5): 387.
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Citation
Selected Articles from This Issue. Mol Cancer Res 1 May 2023; 21 (5): 387. https://doi.org/10.1158/1541-7786.MCR-21-5-HI
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